Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies

François Guérard 1 Laurent Navarro 1 Y.-S. Lee 2 Aurélia Roumesy 1 Cyrille Alliot 3, 1 Michel Chérel 1 M.W. Brechbiel 4 Jean-François Gestin 1
1 CRCINA - Département NOHMAD - Equipe 13 - Oncologie nucléaire
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
2 Center for Molecular Modeling - Office of Intramural Research [Bethesda, MA, USA]
3 GIP ARRONAX - Accélérateur pour la Recherche en Radiochimie et Oncologie [Nantes Atlantique]
4 Radioimmune & Inorganic Chemistry Section - Radiation Oncology Branch [Bethesda, MA, USA]
Abstract : In this report we describe the development of an alternative approach to arylstannane chemistry for radiolabeling antibodies with radioiodine or astatine based on aryliodonium salts precursors. Bifunctional aryliodonium salts were designed and tested for the synthesis of 125 I and 211 At labeled prosthetic groups for bioconjugation. The nature of the electron rich aryl group was varied and its impact on the regioselectivity of radiohalogenation was evaluated. Unexpectedly, whereas the 2-thienyl group provided the best regioselectivity towards the radioiodination of the aryl moiety of interest (98:2), it was less selective for astatination (87:13); the anisyl group providing the best regioselectivity in this case (94:6). Under optimized conditions, both radioiodination and astatination could be performed very efficiently in mild conditions (radiochemical yields > 85%). The ionic nature of the precursors was exploited to develop an efficient purification approach: the HPLC step that is usually necessary in conventionnal approaches to optimize removal of organotin toxic precursors and side products was replaced by a filtration through a silica cartridge with a significantly reduced loss of radiolabeled product. The purified radioiodinated and astatinated prosthetic groups were then conjugated efficiently to an anti-CD138 monoclonal antibody (75-80% conjugation yield). By using this novel and simple radiohalogenation procedure, higher overall radiochemical yields of astatination were obtained in comparison with the use of an arylstannane precursor and procedures of the litterature for labeling the same antibody. Overall, due to their simplicity of use and high robustness, these new precursors should simplify the labeling of proteins of interest with iodine and astatine radioisotopes for imaging and therapeutic applications.
Keywords : radiolabeled antibodies Iodonium salts radioiodination astatination
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François Guérard, Laurent Navarro, Y.-S. Lee, Aurélia Roumesy, Cyrille Alliot, et al.. Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies. Bioorganic and Medicinal Chemistry, Elsevier, 2017, Epub ahead of print. ⟨10.1016/j.bmc.2017.09.022⟩. ⟨inserm-01592684⟩

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